ANTIPLATELET FUNCTIONS OF A STABLE PROSTACYCLIN ANALOG, SM-10906 ARE EXERTED BY ITS INHIBITORY EFFECT ON INOSITOL 1,4,5-TRISPHOSPHATE PRODUCTION AND CYTOSOLIC CA++ INCREASE IN RAT PLATELETS STIMULATED BY THROMBIN

The mechanism of the antiplatelet functions of SM-10906, the active form of the 3-oxa-methano-prostaglandin (PG) II analog SM-10902, was examined in rat platelets. SM-10906 activated adenylate cyclase in crude membrane fractions, and inhibited platelet aggregation and release of adenine nucleotides stimulated by thrombin. SM-10906 also inhibited malondialdehyde production induced by thrombin, but not that induced by arachidonic acid. This may account for its inhibitory effects on phospholipase A2. SM-10906 prevented thrombin-induced inositol 1,4,5-trisphosphate production, Ca++ mobilization from intracellular Ca storage and Ca-45(++) influx into platelets, which were all reversed by pretreatment with the adenylate cyclase inhibitor 2',5'-dideoxyadenosine. PGI2 and PGE1 have the same antiplatelet profiles in the order of PGI2 greater than or equal to SM-10906 > PGE1. These results indicate that SM-10906 as well as PGI2 and PGE1 may exert antiplatelet activities by stimulating adenylate cyclase to prevent thrombin-induced phospholipase C and A2 activations and increase in cytosolic Ca++ level.